The PTEN protein has been implicated as a tumor suppressor in neoplasms of various organs. PTEN is recognized as the susceptibility locus for some hamartomatous polyposis syndromes including cases of familial Juvenile Polyposis Syndrome (JPS). Understanding the pathogenesis of tumorigenesis in JPS is important because of the significant increased lifetime risk for colorectal cancer in JPS patients. Our hypothesis is that PTEN acts as a classic tumor suppressor gene in the histologically benign-appearing hamartomas from patients with germ-line PTEN mutations in that its second allele is inactivated in hamartomas. Because we have identified microsatellite instability within the epithelial portion of the polyps, inactivation of the second PTEN allele might be from inactivation of a component of the DNA mismatch repair system, a system which recognizes and directs repair of DNA after its replication. We propose to directly test this hypothesis by transfecting wild-type PTEN into mismatch repair-defective cell lines with major and minor mismatch repair protein disruptions to assess for inactivation of PTEN. An understanding of the molecular events involved in the role of DNA repair and the somatic inactivation of PTEN may enhance our understanding of the development of the cancer cell, and provide a mechanism for the increased cancer risk in familial hamartomatous syndromes. This application is designed to pursue advances in our understanding of the pathogenesis of hamartomatous polyposis syndromes as well as provide a foundation for the P.I.'s development as an independent physician scientist. The P.I. is dedicated to a career in academic science, and was recognized for her potential as a physician scientist by receiving the American Digestive Health Foundation Fellow/Faculty Transition Award. Since the completion of her clinical training in Pediatric Gastroenterology, the P.I. has engaged in basic science research in the laboratories of John M. Carethers, M.D., a leader in the field of gastrointestinal oncology. Dr. Carethers' research focuses on mechanisms of tumorigenesis, including the biology and genetics of colon cancer, the pathogenesis of hamartomatous polyposis syndromes, and function of the DNA mismatch repair system. Ongoing studies in Dr. Carethers' laboratory complement the proposed studies, creating a stimulating setting that will enhance the P.I.'s scientific education. The P.I. will also be co-mentored by Dr. C. Richard Boland, Associate Director of the Cancer Center at UCSD. He is well regarded in colon cancer genetics and will provide senior supervision to the applicant. Outstanding scientific resources at the University of California, San Diego, including those offered by the Comprehensive Cancer Center, will allow the P.I. to develop collaborations, participate in conferences, and to explore new technology.